There are currently about seven nucleoside reverse transcriptase (RT) inhibitors (NRTIs), about three nonnucleoside RT inhibitors (NNRTI) and about six protease inhibitors (PI) officially approved for the treatment of HIV-infected individuals. Reverse transcriptase and protease are virus-encoded enzymes. The clinical efficacy of the individual drugs varies depending on the nature and the molecular target of the drugs.
U.S. Pat. No. 5,268,389 describes certain thiocarboxylate ester compounds that are said to inhibit the replication of HIV. It is alleged that the selectivity of these compounds for HIV-1 is due to a highly specific interaction with HIV-1 RT.
U.S. Pat. No. 5,696,151 is directed to certain carbothioamides which inhibit replication of HIV-1 and reverse transcriptase mutants thereof.
The rapid emergence of HIV-1 strains resistant to several HIV-1-specific RT inhibitors in cell culture and in AIDS patients has caused concern for further development of these inhibitors in the clinic. See, e.g., Balzarini et al, J. Virology 67(9): 5353–5359 (1993) (“Balzarini I”) and Balzarini et al, Virology 192: 246–253 (1993) (“Balzarini II”).
Failure of long-term efficacy of known drugs can be associated with the appearance of dose-limiting and/or long-term side-effects, or more importantly, with the emergence of drug-resistant virus strains. Both RT inhibitors and protease inhibitors tend to select for virus strains that show a reduced susceptibility for the particular drugs. Moreover, a considerable cross-resistance exists between drugs that act against the same target.
Attempts have been made to combine various HIV-1 RT inhibitors to eliminate virus resistance. See, e.g., Balzarini I, supra. However, there is still a need for new compounds for the treatment of HIV, HCMV, HHV-6, and other retroviruses.
It is a purpose of this invention to provide compositions and methods of preventing or treating HIV-1, HIV-2, HCMV, or HHV-6 infections.